title: Characterization of the transcriptional regulation of the human MT1-MMP gene and association of risk reduction for focal-segmental glomerulosclerosis with two functional promoter SNPs.
abstract: BACKGROUND
  The matrix metalloproteinase MT1-MMP (MMP-14) is an important player in wound healing, bone development, angiogenesis, inflammation and tumour invasion. MT1-MMP also plays an important role in the development and resolution of experimental kidney diseases. The role of MT1-MMP was investigated for distinction between minimal-change glomerulonephritis (MCGN) and focal-segmental glomerulosclerosis (FSGS) that can sometimes be difficult due to sampling error in renal biopsy.
  
  
  METHODS
  We defined the transcriptional regulation of the human MT1-MMP and the influence of single nucleotide polymorphisms (SNPs) within its promoter region in renal mesangial cells with reporter gene constructs and gel sift analysis. Genomic DNA from healthy blood donors (n = 500) and from kidney biopsies with defined renal diseases (MCGN: n = 189, FSGS: n = 311) was screened for MT1-MMP promoter SNPs.
  
  
  RESULTS
  Transcription of MT1-MMP is regulated by two enhancers, an Sp1 binding site and a regulatory region 1 (RR1). RR1 contains an Ets site binding the transcription factors Elf-1 and E1AF but not NFAT. The MT1-MMP promoter contains two SNPs (-378 T/C and -364 G/T) in close vicinity to the RR1. Occurrence of the SNP variant -378 C leads to strong inhibition of nuclear protein binding to the RR1 reducing its enhancer function. Appearance of either variant -378 C or variant -364 T in at least one copy of the MT1-MMP promoter was associated with a significant risk reduction for the development of FSGS (P < 0.048).
  
  
  CONCLUSIONS
  Genetic testing for MT1-MMP promoter SNPs could put renal biopsy results into new perspective. An independent study will be required to verify these findings and their possible diagnostic value for differentiation between certain renal diseases.
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. harendza@uke.de
authors.forename: Astrid
authors.initials: A
authors.lastname: Munkert
authors.forename: Udo
authors.initials: U
authors.lastname: Helmchen
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.forename: Michael
authors.initials: M
authors.lastname: Bubenheim
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.forename: Sigrid
authors.initials: S
authors.lastname: Harendza
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics* / Q000378:metabolism; D050527:Mesangial Cells / Q000502:physiology; D008875:Middle Aged; D009402:Nephrosis, Lipoid / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14